Indole derivatives as dopamine D4 antagonists

ABSTRACT

Compounds of formula (I), or a salt or prodrug thereof, wherein R represent hydrogen or C 1-6  alkyl; Q represents a moiety of formula Qa or Qb; they are antagonists of dopamine receptor subtypes within the brain, having a selective affinity for the dopamine D 4  receptor subtype over other dopamine receptor subtypes, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia whilst manifesting fewer side-effects than those associated with classical neuroleptic drugs. ##STR1##

This is the national stage application of PCT/GB94/00527 filed Mar. 16,1994 and published as WO94/21627 Sep. 29, 1994.

This invention relates to a particular class of heteroaromaticcompounds. More particularly, the invention is concerned with the use ofsubstituted indole derivatives which are antagonists of dopaminereceptor subtypes within the brain and are therefore of benefit in thetreatment and/or prevention of psychotic disorders such asschizophrenia.

The "dopamine hypothesis" of schizophrenia predicts an increasedactivity of dopamine neurotransmission in the disease. The hypothesis issupported by early observations that drugs, such as amphetamine, withdopamine agonist or dopamine-releasing properties are capable ofeliciting a psychosis indistinguishable from acute paranoidschizophrenia.

Schizophrenia is a disorder which is conventionally treated with drugsknown as neuroleptics. In the majority of cases, the symptoms ofschizophrenia can be treated successfully with so-called "classical"neuroleptic agents such as haloperidol. Classical neuroleptics generallyare antagonists at dopamine D₂ receptors. The fact that classicalneuroleptic drugs have an action on dopamine receptors in the brain thuslends credence to the "dopamine hypothesis" of schizophrenia.

Molecular biological techniques have revealed the existence of severalsubtypes of the dopamine receptor. The dopamine D₁ receptor subtype hasbeen shown to occur in at least two discrete forms. Two forms of the D₂receptor subtype, and at least one form of the D₃ receptor subtype, havealso been discovered. More recently, the D₄ (Van Tol et al., Nature(London), 1991, 350, 610) and D₅ (Sunahara et al., Nature (London),1991, 350, 614) receptor subtypes have been described.

Notwithstanding their beneficial antipsychotic effects, classicalneuroleptic agents such as haloperidol are frequently responsible foreliciting acute extrapyramidal symptoms and neuroendocrine disturbances.These side-effects, which clearly detract from the clinical desirabilityof classical neuroleptics, are believed to be attributable to D₂receptor blockade in the striatal region of the brain. It is considered(Van Tol et al., supra) that compounds which can interact selectivelywith the dopamine D₄ receptor subtype, whilst having a less-pronouncedaction at the D₂ subtype, might be free from, or at any rate less proneto, the side-effects associated with classical neuroleptics, whilst atthe same time maintaining a beneficial level of antipsychotic activity.

The compounds in accordance with the present invention, beingantagonists of dopamine receptor subtypes within the brain, areaccordingly of benefit in the treatment and/or prevention of psychoticdisorders such as schizophrenia. Moreover, the compounds according tothe invention have a selective affinity for the dopamine D₄ receptorsubtype over other dopamine receptor subtypes, in particular the D₂subtype, and can therefore be expected to manifest fewer side-effectsthan those associated with classical neuroleptic drugs.

In GB-A-2083476 there is described inter alia a class of3-[piperidin-1-ylmethyl]-1H-indole and3-[1,2,3,6-tetrahydropyrid-1-ylmethyl]-1H-indole derivatives,substituted at the 4-position respectively of the piperidine ortetrahydropyridine moiety by an optionally substituted phenyl group.These compounds are stated to exhibit psychotropic activity and, in somecases, anti-depressant activity. There is, however, no suggestion inGB-A-2083476 that the compounds described therein might be antagonistsof dopamine receptor subtypes within the brain, and thus be of benefitin the treatment and/or prevention of psychotic disorders such asschizophrenia, still less that in doing so they might be expected tomanifest fewer side-effects than those exhibited by classicalneuroleptic agents. Indeed, certain of the compounds described inGB-A-2083476 are explicitly stated to show dopamine agonist activity.

The generic disclosure of EP-A-0449186 encompasses inter alia a seriesof substituted piperidin-1-ylalkyl-indole derivatives which are statedto be antipsychotic agents that act by selective antagonism of the sigmareceptor. There is, however, no specific disclosure therein of a[4-substituted-piperidin-1-ylmethyl]-1H-indole derivative. Moreover,there is no suggestion in EP-A-0449186 that the compounds describedtherein might solve the problem of providing antagonists of dopaminereceptor subtypes within the brain, in particular agents having aselective affinity for the dopamine D₄ receptor subtype over otherdopamine receptor subtypes. Indeed, it is explicitly stated inEP-A0449186 that the compounds described therein do not bind to thedopamine receptors or only have weak binding for the dopamine receptors.

JP-A-61-227565 and JP-A-64-52718 describe in generic terms various[4-substituted-piperidin-1-yl-alkyl]-indole derivatives, which arestated to be effective against certain cardiovascular complaints. Thereis, however, no suggestion in either of these publications that thecompounds described therein might be of benefit in the treatment and/orprevention of disorders of the central nervous system, in particularpsychotic disorders such as schizophrenia.

The present invention accordingly provides a compound of formula I, or asalt or prodrug thereof: ##STR2## wherein R represents hydrogen or C₁₋₆alkyl;

Q represents a moiety of formula Qa or Qb: ##STR3## in which the brokenline represents an optional chemical bond; R¹ represents hydrogen, or anoptionally substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, aryl (C₁₋₆) alkyl, aryloxy (C₁₋₆) alkyl, aryl (C₁₋₆)alkoxy, aryl (C₁₋₆) alkylthio, aryl (C₂₋₆) alkenyl, aryl (C₂₋₆) alkynyl,C₃₋₇ heterocycloalkyl (C₁₋₆) alkyl, heteroaryl, heteroaryl (C₁₋₆) alkyl,heteroaryl (C₂₋₆) alkenyl or heteroaryl (C₂₋₆) alkynyl group;

R² represents an optionally substituted C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl or C₃₋₇ heterocycloalkyl (C₁₋₆) alkyl group; or aryl (C₂₋₆)alkyl, aryloxy (C₁₋₆) alkyl, aryl (C₁₋₆) alkoxy, aryl (C₁₋₆)alkylthio,aryl (C₂₋₆)alkenyl, aryl (C₂₋₆)alkynyl, heteroaryl (C₂₋₆)alkyl,heteroaryl (C₂₋₆) alkenyl or heteroaryl (C₂₋₆) alkynyl, any of whichgroups may be optionally substituted on the aromatic moiety;

R⁶ represents an optionally substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, aryl (C₁₋₆) alkyl, aryloxy (C₁₋₆) alkyl,aryl (C₁₋₆) alkoxy, aryl (C₁₋₆)alkylthio, aryl (C₂₋₆)alkenyl, aryl(C₂₋₆) alkynyl, C₃₋₇ heterocycloalkyl (C₁₋₆) alkyl, heteroaryl,heteroaryl (C₁₋₆) alkyl, heteroaryl (C₂₋₆) alkenyl or heteroaryl (C₂₋₆)alkynyl group;

R³, R⁴ and R⁵ independently represent hydrogen, hydrocarbon, aheterocyclic group, halogen, cyano, trifluoromethyl, nitro, --OR^(a),--SR^(a), --SOR^(a), --SO₂ R^(a), --SO₂ NR^(a) R^(b), --NR^(a) R^(b),--NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --COR^(a), --CO₂ R^(a) or--CONR^(a) R^(b) ; and

R^(a) and R^(b) independently represent hydrogen, hydrocarbon or aheterocyclic group.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoicacid, oxalic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g. quaternary ammonium salts.

The term "hydrocarbon" as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl,aryl(C₂₋₆)alkenyl and aryl(C₂₋₆)alkynyl.

The expression "a heterocyclic group" as used herein includes cyclicgroups containing up to 18 carbon atoms and at least one heteroatompreferably selected from oxygen, nitrogen and sulphur. The heterocyclicgroup suitably contains up to 15 carbon atoms and conveniently up to 12carbon atoms, and is preferably linked through carbon. Examples ofsuitable heterocyclic groups include C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,heteroaryl(C₂₋₆)alkenyl and heteroaryl(C₂₋₆)alkynyl groups.

Suitable alkyl groups within the scope of the term "hydrocarbon" andwithin the definition of the substituents R, R¹ and R⁶ includestraight-chained and branched alkyl groups containing from 1 to 6 carbonatoms. Typical examples include methyl and ethyl groups, andstraight-chained or branched propyl and butyl groups. Particular alkylgroups are methyl, ethyl, n-propyl, isopropyl and t-butyl.

Suitable alkenyl groups within the scope of the term "hydrocarbon" andwithin the definition of the substituents R¹, R² and R⁶ includestraight-chained and branched alkenyl groups containing from 2 to 6carbon atoms. Typical examples include vinyl and allyl groups.

Suitable alkynyl groups within the scope of the term "hydrocarbon" andwithin the definition of the substituents R¹, R² and R⁶ includestraight-chained and branched alkynyl groups containing from 2 to 6carbon atoms. Typical examples include ethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbonatoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Particular aryl groups within the scope of the term "hydrocarbon" andwithin the definition of the substituents R¹ and R⁶ include phenyl andnaphthyl.

Particular aryl-alkyl groups within the scope of the term "hydrocarbon"and within the definition of the substituents R¹, R² and R⁶ includebenzyl, naphthylmethyl, phenethyl and phenylpropyl.

A particular aryl(C₂₋₆)alkenyl group within the scope of the term"hydrocarbon" and within the definition of the substituents R¹, R² andR⁶ is phenylethenyl.

A particular aryl(C₂₋₆)alkynyl group within the scope of the term"hydrocarbon" and within the definition of the substituents R¹, R² andR⁶ is phenylethynyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidyl,piperidyl, piperazinyl, morpholinyl and tetrahydrofuryl groups.

A particular C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl group within the scope ofthe expression "a heterocyclic group" and within the definition of thesubstituents R¹, R² and R⁶ is tetrahydrofurylethyl.

Suitable heteroaryl groups within the scope of the expression "aheterocyclic group" and within the definition of the substituents R¹ andR⁶ include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, oxadiazolyland thiadiazolyl groups.

Particular heteroaryl-alkyl groups within the scope of the expression "aheterocyclic group" and within the definition of the substituents R¹, R²and R⁶ include thienylmethyl, thienylethyl, furylethyl, pyridylmethyl,pyridylethyl, pyrimidinylmethyl and pyrazinylmethyl.

The hydrocarbon and heterocyclic groups, as well as the substituents R¹,R² and R⁶, may in turn be optionally substituted by one or more groupsselected from C₁₋₆ alkyl, adamantyl, phenyl, aryl(C₁₋₆)alkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, trifluoromethyl, hydroxy, C₁₋₆ alkoxy,aryloxy, keto, C₁₋₃ alkylenedioxy, nitro, cyano, carboxy, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆ alkylcarbonyloxy,arylcarbonyloxy, C₂₋₆ alkylcarbonyl, arylcarbonyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, arylsulphonyl,trifluoromethanesulphonyloxy, --NR^(v) R^(w), --NR^(v) COR^(w), --NR^(v)CO₂ R^(w), --NR^(v) SO₂ R^(w), --CH₂ NR^(v) SO₂ R^(w), --NHCONR^(v)R^(w), --PO (OR^(v)) (OR^(w)), --CONR^(v) R^(w), --SO₂ NR^(v) R^(w) and--CH₂ SO₂ NR^(v) R^(w), in which R^(v) and R^(w) independently representhydrogen, C₁₋₆ alkyl, aryl or aryl(C₁₋₆)alkyl.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially chlorine.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof are encompassedwithin the scope of the present invention.

Suitably, the substituent R represents hydrogen or methyl, especiallyhydrogen.

Suitably, the substituent R¹ represents hydrogen.

Suitably, the substituent R² represents aryl(C₂₋₆)alkyl,aryloxy(C₁₋₆)alkyl, aryl(C₁₋₆)alkoxy, aryl(C₁₋₆)alkylthio,aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl or heteroaryl(C₂₋₆)alkyl, any ofwhich groups may be optionally substituted on the aromatic moiety.Examples of optional substituents on the group R² include C₁₋₆ alkyl,halogen, trifluoromethyl, C₁₋₆ alkoxy, nitro, C₁₋₆ alkylamino anddi(C₁₋₆)alkylamino. Particular values of R² include phenethyl,phenylpropyl, phenoxymethyl, benzyloxy, benzylthio, phenylethenyl,phenylethynyl and furylethyl.

Suitable values for the substituents R³, R⁴ and R⁵ include hydrogen,halogen, cyano, nitro, trifluoromethyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy and C₂₋₆alkylcarbonyl. Particular values include hydrogen, fluoro, chloro,methyl, methoxy and benzyloxy.

Suitably, the substituent R⁶ represents aryl(C₁₋₆)alkyl, especiallybenzyl or phenethyl.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof: ##STR4## wherein A represents a moiety of formula --C.tbd.C--,--CH═CH--, --E--(CH₂ )_(n) -- or --(CH₂)_(n) --O--;

E represents an oxygen or sulphur atom or a methylene group;

n is 1, 2 or 3;

--X--Y-- represents --CH₂ --CH-- or --CH=C--;

W represents a group of formula (i), (ii), (iii), (iv), (v) or (vi):##STR5## in which V represents oxygen, sulphur or NH; and R¹³ and R¹⁷independently represent hydrogen, halogen, cyano, nitro,trifluoromethyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkyl,C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy or C₂₋₆ alkylcarbonyl.

Particular values of R¹³ include hydrogen, fluoro, chloro, methyl,ethyl, methoxy and benzyloxy.

Particular values of R¹⁷ include hydrogen, chloro, methoxy and nitro.

One subset of the compounds of formula IIA as defined above isrepresented by the compounds of formula IIB, and salts and prodrugsthereof: ##STR6## wherein A, X, Y, R¹³ and R¹⁷ are as defined withreference to formula IIA above.

In a subset of the compounds of formula IIB above, A represents a moietyof formula --E--(CH₂)_(n) --, in which E represents an oxygen atom or amethylene group.

Another sub-class of compounds according to the invention is representedby the compounds of formula IIC, and salts and prodrugs thereof:##STR7## wherein n, R¹³ and R¹⁷ are as defined with reference to formulaIIA above.

Specific compounds within the scope of the present invention include:

3-[4-(2-phenylethyl)piperidin-1-yl]methyl-1H-indole;

3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

3-(4-benzyloxypiperidin-1-yl)methyl-1H-indole;

7-chloro-3-[4-(2-phenylethyl)piperidin-1-yl]methyl-1H-indole;

7-chloro-3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

(E)-3-[4-(2-phenylethenyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

3-[4-(2-phenylethynyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

3-(4-phenoxymethyl-1,2,3,6-tetrahydropyrid-1-yl)methyl-1H-indole;

3-(4-benzylthiopiperidin-1-yl)methyl-1H-indole;7-methoxy-3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

6-fluoro-3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

3-[4-(3-phenylpropyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

3-[4-(3-phenylpropylidene)piperidin-1-yl]methyl-1H-indole;

3-[4-(2-(furan-2-yl)ethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the compositions may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of schizophrenia, a suitable dosage level is about 0.01to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds in accordance with the present invention may be preparedby a process which comprises reacting a compound of formula III with acompound of formula IV: ##STR8## wherein R³, R⁴ and R⁵ are as definedabove, Q¹ represents the residue of a moiety of formula Qa or Qb asdefined above, and R^(p) corresponds to the group R as defined above orrepresents a suitable protecting group; in the presence of asubstantially equimolar amount of formaldehyde; followed, whererequired, by removal of the protecting group R^(P) ; and subsequently,if necessary, N-alkylation by standard methods to introduce the moietyR.

The reaction is conveniently carried out by stirring the reactants inaqueous acetic acid, ideally in the presence of a buffer such as sodiumacetate trihydrate, suitably at room temperature.

The formaldehyde may be utilised in the form of paraformaldehyde; or asa solution of formaldehyde in an inert solvent, e.g. 37% aqueousformaldehyde.

The protecting group R^(p), when present, is suitably an acyl moietysuch as acetyl, which can conveniently be removed as necessary bytreatment under strongly basic conditions, e.g. sodium methoxide inmethanol. Alternatively, the protecting group R^(p) may be a carbamoylmoiety such as t-butoxycarbonyl (BOC), which can conveniently be removedas necessary by treatment under mildly acidic conditions.

In an alternative procedure, the compounds according to the presentinvention may be prepared by a process which comprises reacting acompound of formula IV as defined above with a compound of formula V:##STR9## wherein R³, R⁴, R⁵ and R^(p) are as defined above, and Lrepresents a suitable leaving group; followed, where required, byremoval of the protecting group R^(p) ; and subsequently, if necessary,N-alkylation by standard methods to introduce the moiety R.

The leaving group L is suitably a halogen atom, e.g. chlorine orbromine; or a dialkylamino group, e.g. dimethylamino.

When L represents a halogen atom, the reaction between compounds IV andV is conveniently carried out by stirring the reactants under basicconditions in a suitable solvent, for example potassium carbonate inN,N-dimethylformamide, or triethylamine in tetrahydrofuran oracetonitrile. Where L represents a dialkylamino group, the reaction isconveniently effected by heating the reactants in an inert solvent suchas toluene, typically at the reflux temperature of the solvent.

Where they are not commercially available, the starting materials offormula III, IV and V may be prepared by procedures analogous to thosedescribed in the accompanying Examples, or by standard methods wellknown from the art.

It will be appreciated that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further desired compound of formula I using techniquesknown from the art. For example, a compound of formula I wherein R ishydrogen initially obtained may be converted into a compound of formulaI wherein R represents C₁₋₆ alkyl by standard alkylation techniques,such as by treatment with an alkyl iodide, e.g. methyl iodide, typicallyunder basic conditions, e.g. sodium hydride in dimethylformamide, ortriethylamine in acetonitrile.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(-)-di-p-toluoyl-d-tartaric acid, and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds useful in this invention potently inhibit [³ H]-spiperonebinding to human dopamine D₄ receptor subtypes expressed in clonal celllines. [³ H]--Spiperone Binding Studies

Clonal cell lines expressing the human dopamine D₄ receptor subtype wereharvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffercontaining 5 mM MgSO₄ for 20 min on ice. Membranes were centrifuged at50,000g for 15 min at 4° C. and the resulting pellets resuspended inassay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM EDTA, 1.5 mM CaCl₂,5 mM MgCl₂, 5 mM KCl, 120 mM NaCl, and 0.1% ascorbic acid) at 20 mg/mlwet weight. Incubations were carried out for 60 min at room temperature(22° C.) in the presence of 0.05-2 nM [³ H]-spiperone or 0.2 nM fordisplacement studies and were initiated by addition of 20-100 μg proteinin a final assay volume of 0.5 ml. The incubation was terminated byrapid filtration over GF/B filters presoaked in 0.3% PEI and washed with10 ml ice-cold 50 mM Tris-HCl, pH 7.4. Specific binding was determinedby 10 μM apomorphine and radioactivity determined by counting in a LKBbeta counter. Binding parameters were determined by non-linear leastsquares regression analysis, from which the inhibition constant K_(i)could be calculated for each test compound.

The compounds of the accompanying Examples were tested in the aboveassay, and all were found to possess a K_(i) value for displacement of[³ H]-spiperone from the human dopamine D₄ receptor subtype of below 1.5μM.

EXAMPLE 13-(4-[2-Phenylethyl]1,2,3,6-tetrahydropyridin-1-yl)methylindole

To a solution of 4-(2-phenylethyl)-1,2,3,6-tetrahydropyridine (preparedby the method of Oediger and Joop, Leibigs. Ann. Chem., 972, 764, 21)(400 mg, 2.2 mmol) in dry toluene (10ml) was added gramine (370 mg, 2.1mmol) and the reaction heated at reflux overnight. The solvent wasevaporated and the residue chromatographed on silica gel eluting with 2%Et₃ N/EtOAc to give a solid which was recrystallised twice from tolueneto yield the title compound as a white solid (160 mg, 25%), m.p.138-140° C.; (Found: C, 83.59; H, 7.71; N, 8.89. C₂₂ H₂₄ N₂ requires C,83.50; H, 7.64; N, 8.85%); δ_(H) (CDCl₃) 2.13 (2H, br s,tetrahydropyridinyl CH₂), 2.25 (2H, t, J 8.3 Hz, PhCH₂ CH₂), 2.64-2.73(4H, m, tetrahydropyridinyl CH₂, PhCH₂ CH₂), 3.05 (2H, br s,tetrahydropyridinyl CH₂), 3.81 (2H, s, NCH₂ Ar), 5.40 (1H, br s,tetrahydropyridyl CH), 7.11-7.28 (8H, m, ArH), 7.36 (1H, d, J 7.9 Hz,ArH), 7.72 (1H, d, J 7.9 Hz, ArH), and 8.12 (1H, br s, NH); m/z (CI⁺,NH3) 317 (M+1)⁺.

Prepared analogously were:

EXAMPLE 2 3,(4-[2-Phenylethyl]piperidin-1-yl)methylindole

M.p. 142° C. (PhMe); (Found: C, 83.31; H, 8.48; N, 8.71. C₂₂ H₂₆ N₂requires C, 82.97; H, 8.23; N, 8.80%); δ_(H) (DMSO-d₆) 1.11-1.16 (3H, m,piperidinyl CH₂ +CH), 1.46 (2H, m, CH₂ CH₂ Ph), 1.64 (2H, d, J 9.5 Hz,piperidinyl CH₂), 1.84 (2H, t, J 10.1 Hz, piperidinyl CH₂), 2.55 (2H, t,J 7.9 Hz, CH₂ Ph), 2.85 (2H, d, J 11.1 Hz, piperidinyl CH₂), 3.57 (2H,s, N-CH₂ Ar), 6.93-6.98 (1H, m, indole H), 7.02-7.07 (1H, m, indole H),7.12-7.14 (4H, m, ArH), 7.22-7.26 (2H, m, ArH), 7.32 (1H, d, J 8.0 Hz,4-H), 7.60 (1H, d, J 7.8 Hz, 7-H), and 10.86 (1H, br s, NH); m/z (CI⁺,NH₃) 319 (M+1)⁺.

EXAMPLE 3 3-(4-[Benzyloxy]piperidin-1-yl)methylindole

M.p. 143°-145° C. (EtOAc); (Found: C, 78.49; H, 7.54; N, 8.84. C₂₁ H₂₄N₂ O requires C, 78.71; H, 7.55; N, 8.74%); δ_(H) (DMSO-d₆) 1.45-1.51(2H, m, piperidinyl CH₂), 1.82 (2H, m, piperidinyl CH₂), 2.07 (2H, t, J9.7 Hz, piperidinyl CH₂), 2.70-2.73 (2H,.m, piperidinyl CH₂), 3.34-3.37(1H, m, piperidinyl CH), 3.59 (2H, s, N--CH₂ Ar), 4.46 (2H, s, OCH₂ Ph),6.94-6.98 (1H, m, indole H), 7.03-7.07 (1H, m, indole H), 7.19 (1H, d, J2.1 Hz, 2-H), 7.23-7.34 (6H, m, ArH), 7.61 (1H, d, J 7.9 Hz, 7-H), and10.87 (1H, br s, NH); m/z (CI⁺, NH₃) 321 (M+1)⁺.

EXAMPLE 4 7-Chloro-3-(4-[2-phenylethyl]piperidin-1-yl)methylindolehydrochloride

Step 1: 7-Chlorogramine

N,N-Dimethylmethylene ammonium chloride (0.94g, 10 mmol) was added to asolution of 7-chloroindole (prepared according to the method of M. Boscoet al, J. Chem. Soc., Perkin Transactions II, 1991, 657) (1.31 g, 8.6mmol) and the mixture stirred at room temperature for 2.5 h. Theresulting suspension was diluted with dichloromethane (20 ml), washedwith saturated aqueous sodium carbonate (25 ml), and the organic layerdried (Na₂ CO₃) and evaporated to leave an orange solid.Recrystallisation from ethyl acetate gave 7-chlorogramine as pale orangerhombs (0.71 g), m.p. 148°-152° C.; δ_(H) (CDCl₃) 2.29 (6H, s, NMe₂),3.64 (2H, s, CH₂ NMe₂), 7.06 (1H, t, J 7.8 Hz, 5-H), 7.19 (1H, d, J 7.8Hz, 6-H), 7.20 (1H, s, 2-H), 7.60 (1H, d, J 7.8 Hz, 4-H), and 8.36 (1H,br s, NH).

Step 2: 7-Chloro-3-(4-[2-phenylethyl]piperidin-1-yl) methylindolehydrochloride

A solution of the aforementioned gramine (208 g, 1 mmol) and4-(2-phenylethyl)piperidine (200 mg, 1 mmol) in toluene (10 ml) wasstirred under reflux for 6.5 h and the solvent removed. The residueremaining was subjected to chromatography on silica gel, eluting with10% methanol and 1% 880 ammonia in dichloromethane, to give the crudeproduct as a yellow solid. This was dissolved in ether and excessethereal HCl added, the precipitated solid collected and recrystallisedfrom methanol to give a white solid, m.p. 240°-242° C. (dec.); (Found:C, 76.71; H, 6.89; N, 4.29. C₂₀ H₂₂ ClN₂ requires C, 77.03; H, 7.11; N,4.49%); δ_(H) (DMSO-d₆) 1.41-1.49 (3H, m, piperidinyl CH₂ and CH), 1.86(2H, m, CH₂ CH₂ Ph), 2.57 (2H, t, J 7.0 Hz, CH₂ CH₂ Ph), 2.88 (2H, m,piperidinyl CH₂), 3.16-3.29 (2H, m, piperidinyl CH₂), 3.39 (2H, m,piperidinyl CH₂), 4.40 (2H, br s, CH₂ N), 7.10-7.28 (7H, m, ArH), 7.68(1H, br s, ArH), 7.77 (1H, d, J 8.0 Hz, ArH), and 11.86 (1H, br s, NH);m/z (CI⁺, NH₃) 353 (M+1)⁺.

EXAMPLE 57-Chloro-3-(4-[2-phenylethyl]1-1,2,3,6-tetrahydropyridin-1-yl)methylindole

M.p. 164°-166° C. (PhMe); (Found: C, 75.41; H, 6.55; N, 7.78. C₂₂ H₂₃ClN₂ requires: C, 75.31; H, 6.61; N, 7.98%); δ_(H) (CDCl₃) 2.04 (2H, m,CH₂), 2.15-2.19 (2H, m, CH₂), 2.49-2.65 (4H, m, 2×CH₂), 2.93 (2H, br s,CH₂), 3.70 (2H, br s, CH₂ N), 5.30 (1H, br s, CH═CR), 6.93 (1H, t, J 7.7Hz, 4'-H), 7.04-7.09 (3H, m, ArH), 7.15-7.20 (3H, m, ArH), 7.53 (1H, d,J 7.9 Hz, ArH) and 10.18 (1H, br s, NH); m/z (CI⁺, NH₃) 351 (M+1)⁺.

EXAMPLE 6(E)-3-(4-[2-Phenylethenyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindole

M.p. 191°-193° C. (PhMe); (Found: C, 84.12; H, 6.74; N, 8.77. C₂₂ H₂₂ N₂requires C, 84.04; H, 7.05; N, 8.91%); δ_(H) (CDCl₃) 2.43 (2H, br s,CH₂), 2.74-2.78 (2H, m, CH₂), 3.23 (2H, br s, CH₂), 3.86 (2H, s, CH₂ N),5.81 (1H, s, CH═CR), 6.43 (1H, d, J 16.2 Hz, CH═CHPh), 6.78 (1H, d, J16.3 Hz, CH═CHPh), 7.13-7.31 (6H, m, ArH), 7.37-7.40 (3H, m, ArH), 7.75(1H, d, J 8.0 Hz, 7-H), and 8.11 (1H, br s, NH); m/z (CI⁺, NH₃) 315(M+1)⁺.

EXAMPLE 73-(4-[2-Phenylethynyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindole

Step 1: 4-Phenylethynylpyridine

A mixture of 4-bromopyridine hydrochloride (9.75 g, 50 mmol),phenylacetylene (11 ml, 10.2 g; 100 mmol), copper (I) iodide (50 mg) andbis(triphenylphosphino)palladium (II) chloride (200 mg) in drytriethylamine (60 ml) was stirred under reflux for 16 h, the cooledreaction mixture filtered, and the filtrate evaporated. The residualblack oil was dissolved in ethyl acetate (100 ml) and washed withsaturated aqueous sodium carbonate (2×50 ml) and HCl (1M, 4×25 ml). Theacidic washings were extracted with ethyl acetate (2×25 ml) and thenbasified (5M NaOH). The resulting suspension was extracted withdichloromethane (4×25 ml), the combined organic layers washed with water(25 ml), dried (MgSO₄), evaporated, and the residue chromatographed onsilica gel, eluting with 7:3 ethyl acetate/60°-80° petrol to give theproduct as a buff solid (2.79 g, 31%).

Step 2: 1-Benzyl-4-(2-phenylethynyl)-1,2,3,6-tetrahydropyridine

A solution of benzyl bromide (2.0 ml, 2.91 g, 17 mmol) and4-(2-phenylethynyl)pyridine (2.68 g, 15 mmol) in DMF (10 ml) was stirredfor 1 h at 100° C. On cooling, ethanol (65 ml) was added to theresulting paste, followed by portionwise addition of sodium borohydride(0.76 g, 20 mmol). After stirring for 2 h at room temperature and 1 h atreflux, the mixture was allowed to cool, filtered, and the filtrateevaporated. The residue was partitioned between ethyl acetate (50 ml)and water (2×25 ml), the organic layer dried (MgSO₄) and evaporated, andthe residue chromatographed, eluting with 15% ethyl acetate in 60°-80°C. petrol, to give the desired product as a pale brown solid (2.49 g,61% A sample of the hydrogen oxalate was prepared for characterisation;m.p. 217° C. (dec.) (MeOH); (Found: C, 72.80; H, 5.68; N, 13.68. C₂₂ H₂₁NO₄ requires C, 72.71; H, 5.82; N, 3.85%).

Step 3: 4-(2-Phenylethynyl)-1,2,3,6-tetrahydropyridine

The aforementioned N-benzyl derivative was debenzylated by the method ofOediger and Joop, Liebigs Ann, Chim., 1972, 764, 21 to give the productas a gum; δ_(H) (CDCl₃) 2.31-2.35 (2H, m, 3--CH₂), 2.55 (1H, br s, NH),3.05 (2H, t, J 5.7 Hz, 6--CH₂), 3.50-3.52 (2H,.m, 2-H), 6.16-6.19 (1H,m, 5-H), 7.29-7.32 (3H, m, 2',4',6'-H), and 7.41-7.44 (2H, m, 3',5'-H).

Step 4: 3-(4-[2-Phenylethynyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindole hydrogen oxalate

A solution of 4-(2-phenylethynyl)-1,2,3,6-tetrahydropyridine (177 mg,0.97 mmol) and gramine (174 mg, 1 mmol) in toluene (15 ml) was stirredunder reflux overnight, and the solution then evaporated. The residuewas chromatographed, eluting with 10% methanol in dichloromethane toleave the product as a brown gum (262 mg). This was convened to thehydrogen oxalate salt; m.p. 68° C. (dec.) (MeOH/Et₂ O); (Found: C,71.64; H, 5.52; N, 6.92. C₂₄ H₂₂ N₂ O₄ requires C, 71.63; H, 5.51; N,6.96%); δ_(H) (DMSO-d₆) 2.49-2.51 (2H, m, CH₂), 3.18 (2H, br s, CH₂),3.63 (2H, m, CH₂), 4.35 (2H, br s, CH₂ N), 6.16 (1H, br s, CH═CR),7.07-7.17 (2H, m, ArH), 7.38-7.46 (6H, m, ArH), 7.52 (1H, s, 2-H), 7.75(1H, d, J 7.7 Hz, 7-H), and 11.39 (1H, br s, NH); m/z (CI⁺, NH₃) 313(M+1)⁺.

EXAMPLE 8 3-(4-Phenoxymethyl-1,2,3,6-tetrahydropyridin-1-yl)methylindole

Prepared in an analogous manner to that described for the previouscompound. M.p. 140°-142° C. (PhMe); (Found: C, 79.26; H, 6.91; N, 8.57.C₂₁ H₂₂ N₂ O requires C, 79.21; H, 6.96; N, 8.80%); δ_(H) (CDCl₃) 2.24(2H, br s, 3'--CH₂), 2.69-2.72 (2H, m, 2'--CH₂), 3.11 (2H, br s,6'--CH₂), 3.83 (2H, s, CH₂ N), 4.39 (2H, s, CH₂ OPh), 5.77 (1H, t, J 1.4Hz, CH═CR), 6.88-6.94 (3H, m, ArH), 7.10-7.37 (5H, m, ArH), 7.36 (1H,dd, J 8.0, 0.7 Hz, 4-H), 7.73 (1H, d, J 7.1 Hz, 7-H), and 8.13 (1H, brs, NH); m/z (CI⁺, NH₃) 319 (M+1)⁺.

EXAMPLE 9 3-(4-Phenylmethylthiopiperidin-1-yl)methylindole hydrochloride

Step 1: N-Boc-(4-bromo)piperidine

To N-Boc-4-hydroxy piperidine (20 g, 100 mmol) in THF (200 ml) at 0° C.was added triphenylphosphine (28.85 g, 110 mmol) followed by carbontetrabromide (36.48 g, 110 mmol). The solution was stirred at roomtemperature for 2 h then filtered and concentrated under vacuum. Flashcolumn chromatography using dichloromethane in hexane (10-70%) yieldedthe product as a colourless oil (23.6 g); δ_(H) (CDCl₃) 1.47 (9H, s,t-Bu), 1.93 and 2.04 (4H, m, 3,5-piperidinyl CH₂), 3.31 and 3.66 (4H, m,2,6-piperidinyl CH₂), and 4.39 (1H, m, 4-piperidinyl H).

Step 2: N-Boc-4-benzylthiopiperidine

To benzyl mercaptan (17 ml, 152 mmol)in dimethylformamide at 0° C. undernitrogen was added sodium hydride (80% dispersion in mineral oil, 4.38g, 152 mmol) the solution was stirred at room temperature for 15 minutesthen cooled to 0° C. prior to adding N-Boc-(4-bromo)piperidine (10.8 g,38 mmol). The mixture was stirred for 14 h at room temperature thenpoured into water (50 ml), extracted with diethyl ether (2×100 ml), theorganic layers combined, dried (MgSO₄), filtered, evaporated, and thecrude product purified by flash column chromatography using 10% ethylacetate in hexane to yield the product as a pale yellow oil (2.86 g);δ_(H) (CDCl₃) 1.46 (9H, s, t-Bu), 1.51 and 1.87 (4H, m, 3,5-piperidinylCH₂), 2.85 and 3.91 (4H, m, 2,6-piperidinyl CH₂), 2.69 (1H, m,4-piperidinyl H), 3.77 (2H, s, SCH₂), and 7.24-7.32 (5H, m, ArH).

Step 3: 3-(4-Phenylmethylthiopiperidin-1-yl)methylindole hydrochloride

To N-Boc-4-benzylthiopiperidine (0.60 g, 1.98 mmol) in diethyl ether wasadded hydrogen chloride in diethyl ether (3 ml, ˜2.5 mmol) dropwise andthe solution allowed to stir for 5 minutes then concentrated undervacuum and the residue partitioned between saturated sodium hydrogencarbonate solution and dichloromethane, the organic layer dried overmagnesium sulphate, filtered and evaporated to dryness. To the residuein dry toluene (50 ml) was added gramine (0.35 g, 2 mmol) and themixture stirred at reflux under nitrogen for 6 h, evaporated and theresidue redissolved in 1:1 methanol and diethyl ether (10 ml), hydrogenchloride in diethyl ether (3 ml, ˜2.5 mmol) added dropwise and thesolution stirred for 5 minutes, partially evaporated and triturated withdiethyl ether. The white precipitate formed was collected andrecrystallised from methanol/diethyl ether to yield the product (90 mg)as a white solid, m.p. 264-266° C.; (Found: C, 66.61; H, 6.26; N, 7.26;C₂₁ H₂₄ N₂ S1.2HCl requires C, 66.33; H, 6.60; N, 7.36% ); δ_(H)(DMSO-d₆) 1.73 and 2.07 (4H, m, 3,5-piperidinyl CH₂), 2.70 (1H, m,4-piperidinyl H), 2.91 and 3.42 (4H, m, 2,6-piperidinyl CH₂), 3.78 (2H,s, SCH₂), 4.41 (2H, s, NCH₂ Ar), and 7.08-7.82 (9H, m, ArH); m/z (CI⁺,NH₃ 336 (M+1)⁺.

EXAMPLE 107-Methoxy-3-(4-[2-phenylethyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindole

M.p. 131°-133° C. (PhMe); (Found: C, 79.63; H, 7.47; N, 7.88. C₂₃ H₂₆ NOrequires C, 79.73; H, 7.56; N, 8.09%); δ_(H) (CDCl₃) 2.16 (2H, br s,tetrahydropyridinyl 3--CH₂), 2.26 (2H, t, J 7.3 Hz, tetrahydropyridinyl2-CH₂), 2.69-2.73 (4H, m, PhCH₂ CH₂), 3.08 (2H, br s,tetrahydropyridinyl 6-CH₂), 3.84 (2H, s, NCH₂ Ar), 3.96 (3H, s, OCH₃),5.39 (1H, br s, CH═CR), 6.65 (1H, d, J 7.7 Hz, ArH), 7.05 (1H, t, J 7.9Hz, ArH), 7.15-7.18 (3H, m, ArH), 7.24-7.30 (4H, m, ArH), and 8.34 (1H,br s, NH); m/z (CI⁺, NH₃) 347 (M+1)⁺.

EXAMPLE 116-Fluoro-3-(4-[2-phenylethyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindole

M.p. 150°-152° C. (PhMe); (Found: C, 79.33; H, 6.68; N, 7.93. C₂₂ H₂₃FN₂ requires C, 79.01; H, 6.93; N, 8.37%); δ_(H) (CDCl₃) 2.13 (2H, br s,tetrahydropyridinyl 3-CH₂), 2.26 (2H, t, J 8.2 Hz, PhCH₂ CH₂), 2.61-2.64(2H, m, tetrahydropyridinyl 2-CH₂), 2.71 (2H, t, J 8.2 Hz, PhCH₂ CH₂),3.02 (2H, br s, tetrahydropyridinyl 6-CH₂), 3.77 (2H, s, NCH₂ Ar), 5.39(1H, br s, tetrahydropyridinyl 5-CH), 6.88 (1H, t, J 8.0 Hz, ArH), 7.03(1H, d, J 9.6 Hz, ArH), 7.15-7.17 (4H, m, ArH), 7.24-7.28 (2H, m, ArH),7.61-7.65 (1H, m, ArH), and 8.08 (1H, br s, NH); m/z (CI⁺, NH₃), 335(M+1)⁺.

EXAMPLE 12 3-(4-[3-Phenylpropyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindole oxalate

M.p. 171°-172° C. (dec.) (EtOAc); (Found: C, 71.39; H, 6.78; N, 6.59.C₂₃ H₂₆ N₂.(CO₂ H)₂ requires C, 71.41; H, 6.71; N, 6.66%); δ_(H)(DMSO-d₆) 1.67 (2H, m, PhCH₂ CH₂ CH₂), 2.01 (2H, t, J 7.2 Hz, CH₂), 2.25(2H, s, tetrahydropyridinyl CH₂), 2.54 (2H, m, CH₂), 3.21 (2H, br s,tetrahydropyridinyl CH₂), 3.56 (2H, s, tetrahydropyridinyl CH₂) 4.41(2H, s, NCH₂ Ar), 5.39 (1H, s, tetrahydropyridinyl CH), 7.07-7.18 (5H,m, ArH), 7.23-7.27 (2H, m, ArH), 7.44 (1H, d, J 7.9 Hz, 4-H), 7.54 (1H,d, J 2.1 Hz, 2-H), 7.74 (1H, d J 7.7 Hz, 7-H), and 11.46 (1H, br s, NH);m/z (CI⁺, NH₃) 331 (M+1)⁺.

EXAMPLE 13 3-(4-[3-Phenylpropylidene]piperidin-1-yl)methylindole oxalate

M.p. 170°-171° C. (dec.) (EtOH); (Found: C, 71.10; H, 6.67; N, 6.54. C₂₃H₂₆ N₂. (CO₂ H)₂ requires C, 71.41; H, 6.71; N, 6.66%); δ_(H) (DMSO-d6)2.26 (6H, m, 3×CH₂), 2.57 (2H, t, J 7.3 Hz, CH₂), 2.80-3.00 (4H, m,2×CH₂), 4.32 (2H, s, N--CH₂), 5.27 (1H, t, J 7.2 Hz, PhCH₂ CH₂ CH),7.03-7.18 (7H, m, ArH), 7.45 (1H, d, J 8.0 Hz, 4-H), 7.50 (1H, s, 2-H),7.71 (1H, d, J 7.8 Hz, 7-H), and 11.47 (1H, br s NH); m/z (CI-, NH₃) 329(M-1)⁺.

EXAMPLE 143-(4-[2-(Furan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-1-yl)methylindolehydrochloride

Step 1: (E)-1-(Pyridin-4-yl)-2-(furan-2-yl)ethene

A solution of 4-methylpyridine (15 g, 0.16 mol) in acetic anhydride (100ml) was treated with 2-furaldehyde (15.5 g, 0.16 mol) and heated atreflux for 16 hrs. The solvent was evaporated to give a black oil whichwas treated with water (30 ml) and stirred for 30 mins at roomtemperature. Ethyl acetate (150 ml) and saturated sodium carbonate (100ml)were then added and the stirring continued for 30 mins. The solventswere decanted to leave a black oily residue which was retained (A). Fromthe decanted solvents the organic phase was separated, dried (Na₂ SO₄)and evaporated to give a black oil (B). The oily residue (A) wasdissolved in dichloromethane (150 ml), washed with saturated sodiumcarbonate solution (100 ml), dried (Na₂ SO₄) and evaporated to give ablack oil which was combined with oil (B). The mixture waschromatographed with a gradient of ethyl acetate in hexane (50% -100%)as eluant to afford the title compound as a brown solid (9.8 g, 36%);δ_(H) (DMSO-d6) 6.58-6.64 (1H, m, furanyl H), 6.66-6.72 (1H, m, furanylH), 6.96 (1H, d, J 17.5 Hz, ArCH═CHAr'), 7.42 (1H, d, J 17.5 Hz,ArCH═CHAr'), 6.50-6.58 (2H, m, pyridinyl H), 7.78-7.82 (1H, m, furanylH), and 8.50-8.57 (2H, m, pyridinyl H).

Step 2: 1-(Pyridin-4-yl)-2-(furan-2-yl)ethane

A solution of the foregoing compound (8 g, 46.8 mmol) in methanol (200ml) was treated with ammonium formate (14.7 g, 234.0 mmol). 10%Palladium on charcoal catalyst (400 mg) was added and the mixture wasstirred at reflux for five hours. The catalyst was filtered off and thesolvent evaporated. The residue was partitioned between dichloromethaneand water. The organic layer was separated, dried (MgSO₄) and evaporatedto give a beige oil. This material was chromatographed with a gradientof ethyl acetate in hexane (50% -100%) as eluant to afford the titlecompound as a colourless oil (2.5 g, 31%); δ_(H) (DMSO-d₆) 2.94-3.06(4H, m, 2×CH₂), 6.06-6.12 (1H, m, furanyl H), 6.32-6.38 (1H, m, furanylH), 7.20-7.28 (2H, m, pyridinyl H), 7.50-7.56 (1H, m, furanyl H), and8.40-8.50 (2H, m, pyridinyl H).

Step 3: 1-Benzyl-4-[2-(furan-2-yl)ethyl]-1,2,3,6-tetrahydropyridine

A solution of 1-(pyridinyl)-2-(furan-2-yl)ethane (2 g, 11.6 mmol) inanhydrous dimethylformamide (5 ml)was treated with benzyl bromide (1.5ml, 12.7 mmol) and the reaction stirred at room temperature for onehour. The reaction was diluted with ethanol (50 ml), treated with sodiumborohydride (0.55 g, 14.5 mmol) and heated at reflux for one hour. Thesolvent was evaporated and the residue partitioned between ethyl acetateand water. The organic layer was separated, dried (Na₂ SO₄) andevaporated to give crude product as a yellow oil. This material wastriturated with diethyl ether to afford the title compound (2.3 g, 68%)as a colourless solid; δ_(H) (DMSO-d₆) 1.92-2.10 (2H, m,tetrahydropyridinyl CH₂), 2.14-2.30 (2H, m, CH₂ CH₂), 2.36-2.50 (2H, m,CH₂ CH₂), 2.60-2.82 (2H, m, tetrahydropyridinyl CH₂), 2.84-2.90 (2H, m,tetrahydropyridinyl CH₂), 3.50 (2H br s, ArCH₂ N), 5.32-5.44 (1H, m,tetrahydropyridinyl 5-H), 6.02-6.10 (1H, m, furanyl H), 6.30-6.36 (1H,m, furanyl H), 7.16-7.36 (5H, m, ArH), and 7.44-7.52 (1H, m, furanyl H);m/z (CI⁺, NH₃) 268 (M+1)⁺.

Step 4-[2-(Furan-2-yl)ethyl]-1,2,3,6-tetrahydropyridine

A cooled (0° C.) solution of the product from the previous step (1.8 g,6.8 mmol) in anhydrous dichloromethane (20 ml) was treated with2-chloroethylchloroformate (0.45 ml, 8.8 mmol) dropwise. The mixture wasstirred for 1 hr at 0° C. The solvent was evaporated and the residuedissolved in methanol (60 ml). This solution was heated at reflux forone hour whereupon the solvent was evaporated. The residue waspartitioned between dichloromethane and saturated aqueous potassiumcarbonate solution. The organic phase was separated, dried (Na₂ SO₄) andevaporated to give the title compound (867 mg, 72%) as a colourless oil;δ_(H) (DMSO-d₆) 1.84-1.96 (2H, m, tetrahydropyridinyl CH₂), 2.16-2.30(2H, m, CH₂ CH₂), 2.64-2.80 (4H, m, tetrahydropyridinyl CH₂ and CH₂CH₂), 3.06-3.10 (2H, m, tetrahydropyridinyl CH₂), 5.40-5.46 (1H, m,tetrahydropyridinyl 5-H), 6.06-6.12 (1H, m, furanyl H), 6.32-6.38 (1H,m, furanyl 5-H), and 7.48-7.56 (1H, m, furanyl H).

Step 5:3-(4-[2-(Furan-2-yl)ethyl]-1,2,3,6tetrahydropyridin-1-yl)methylindolehydrochloride

A solution of gramine (775 mg, 4.5 mmol) and4-[2-(furan-2-yl)ethyl]-1,2,3,6-tetrahydropyridine (867 mg, 4.9 mmol) inanhydrous toluene (50 ml) was heated at reflux for sixteen hours. Thesolvent was evaporated and the residue chromatographed with a gradientof methanol in dichloromethane (1-10%) as eluant. The product wasdissolved in dichloromethane (30 ml) and treated with ethereal hydrogenchloride. The solvents were evaporated and the residue triturated withdiethyl ether to afford the title compound (272 mg, 15%) as a colourlesssolid; m.p. 155°-156° C.; (Found: C, 69.09; H, 6.83; N, 7.88. C₂₀ H₂₂ N₂O.HCl.0.25H₂ O requires C, 69.15; H, 6.82; N, 8.06% ); δ_(H)

(DMSO-d₆) 2.20-2.50 (4H, m, tetrahydropyridinyl CH₂ and CH₂ CH₂), 2.72(2H, t, J 7.5 Hz, CH₂ CH₂), 3.00-3.10 (1H, m, tetrahydropyridinyl CH₂),3.40-3.70 (3H, m, tetrahydropyridinyl CH₂), 4.46 (2H, d, J 4.7 Hz,ArCH₂), 5.40-5.45 (1H, m, tetrahydropyridinyl 5-H), 6.12 (1H, d, J 2.3Hz, furanyl H), 6.32-6.34 (1H, m, furanyl H), 7.04-7.20 (2H, m, ArH),7.40-7.50 (2H, m, ArH), 7.65 (1H, d, J 2.7 Hz, ArH), 7.78 (1H, d, J 7.8Hz, ArH), 10.40 (1H, br s, NH), and 11.53 (1H, s, NH⁺); m/z (CI⁺, NH₃)307 (M+1)⁺.

We claim:
 1. A compound of formula I, or a salt or prodrug thereof:##STR10## wherein R represents hydrogen or C₁₋₆ alkyl;Q represents amoiety of formula Qa or Qb: ##STR11## in which the broken linerepresents an optional chemical bond; R¹ represents hydrogen, or anoptionally substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, aryl(C₁₋₆) alkyl, aryloxy(C₁₋₆) alkyl, aryl(C₁₋₆)alkoxy,aryl(C₁₋₆)alkylthio, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl, heteroaryl(C 1-6)alkyl,heteroaryl(C₂₋₆)alkenyl or heteroaryl(C₂₋₆)alkynyl group; R² representsan optionally substituted C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl orC₃₋₇ heterocycloalkyl(C₁₋₆)alkyl group; or aryl(C₂₋₆)alkyl,aryloxy(C₁₋₆)alkyl, aryl(C₁₋₆)alkoxy, aryl(C₁₋₆)alkylthio,aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, heteroaryl(C₂₋₆)alkyl,heteroaryl(C₂₋₆)alkenyl or heteroaryl(C₂₋₆)alkynyl, any of which groupsmay be optionally substituted on the aromatic moiety; R⁶ represents anoptionally substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, aryl(C₁₋₆)alkyl, aryloxy(C₁₋₆)alkyl, aryl(C₁₋₆)alkoxy,aryl(C₁₋₆)alkylthio, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,heteroaryl(C₂₋₆)alkenyl or heteroaryl(C₂₋₆)alkynyl group; R³, R⁴ and R⁵independently represent hydrogen, hydrocarbon, a heterocyclic group,halogen, cyano, trifluoromethyl, nitro, --OR^(a), --SR^(a), --SOR^(a),--SO₂ R^(a), --SO₂ NR^(a) R^(b), --NR^(a) R^(b), --NR^(a) COR^(b),--NR^(a) CO₂ R^(b), --COR^(a), --CO₂ R^(a) or --CONR^(a) R^(b) ; andR^(a) and R^(b) independently represent hydrogen, hydrocarbon or aheterocyclic group.
 2. A compound represented by formula IIA, or saltsor prodrugs thereof: ##STR12## wherein A represents a moiety of formula--C.tbd.C--, --CH═CH--, --E--(CH₂)_(n) -- or --(CH₂)_(n) --O--;Erepresents an oxygen or sulphur atom or a methylene group; n is 1, 2 or3; --X--Y-- represents --CH₂ --CH-- or --CH═C--; W represents a group offormula (i), (ii), (iii ), (iv), (v) or (vi): ##STR13## in which Vrepresents oxygen, sulphur or NH; and R¹³ and R¹⁷ independentlyrepresent hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy,aryl(C₁₋₆)alkoxy or C₂₋₆ alkylcarbonyl.
 3. A compound as claimed inclaim 2 represented by formula IIB, or pharmaceutically acceptable saltsor prodrugs thereof: ##STR14## wherein A, X, Y, R¹³ and R¹⁷ are asdefined in claim
 2. 4. A compound as claimed in claim 1 represented byformula IIC or, and salts or prodrugs thereof: ##STR15## wherein n is 1,2 or 3;R¹³ and R¹⁷ independently represent hydrogen, halogen, cyano,nitro, trifluoromethyl, amino, C₁₋₆ alkylamino, de(C₁₋₆)alkylamino, C₁₋₆alkyl, C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy or C₂₋₆ alkylcarbonyl.
 5. Acompound as claimed in claim 2 wherein R¹³ represents hydrogen, fluoro,chloro, methyl, ethyl, methoxy or benzyloxy.
 6. A compound as claimed inclaim 2 wherein R¹⁷ represents hydrogen, chloro, methoxy or nitro.
 7. Acompound as claimed in claim 1 selectedfrom:3-[4-(2-phenylethyl)piperidin-1-yl]methyl-1H-indole;3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;3-(4-benzyloxypiperidin-1-yl)methyl-1H-indole;7-chloro-3-[4-(2-phenylethyl)piperidin-1-yl]methyl-1H-indole;7-chloro-3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;(E)-3-[4-(2-phenylethenyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;3-[4-(2-phenylethynyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;3-(4-phenoxymethyl-1,2,3,6-tetrahydropyrid-1-yl)methyl-1H-indole;3-(4-benzylthiopiperidin-1-yl)methyl-1H-indole;7-methoxy-3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;6-fluoro-3-[4-(2-phenylethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;3-[4-(3-phenylpropyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;3-[4-(3-phenylpropylidene)piperidin-1-yl]methyl-1H-indole; and3-[4-(2-(furan-2-yl)ethyl)-1,2,3,6-tetrahydropyrid-1-yl]methyl-1H-indole;orsalts or prodrugs thereof.
 8. A pharmaceutical composition comprising acompound as claimed in claim 1 in association with a pharmaceuticallyacceptable carrier.
 9. A method for the treatment and/or prevention ofschizophrenia, which method comprises administering to a patient in needof such treatment an effective amount of a compound as claimed in claim1.